Perinatal Trajectories of Maternal Depressive Symptoms in Prospective, Community-Based Cohorts Across 3 Continents

Key Points Question What is the course and stability of maternal depressive symptoms throughout the perinatal period? Findings This cohort study analyzed maternal depressive symptoms trajectories of 11 563 pregnant women from 7 cohorts across 3 continents and showed 3 distinct clusters of mothers with stable low, mild, and high symptom levels throughout the perinatal period. This trajectory was apparent among participants with clinical symptom levels. Meaning These findings suggest that interventions, guidelines for care, and public health policies aimed at alleviating maternal depressive symptoms should target both pregnancy and the postnatal period.


Statistical analysis
Scree plots (eFigure 1 and eFigure 2) show the total within-clusters sum of squares (WSS) as a function of the number of clusters used in the k-means algorithm.WSS values are obtained by summing the squared deviations of each data point from the cluster center it is assigned to.WSS is an inverse measure of the compactness of a cluster, as points closer to the center yield lower WSS values.Total WSS values are then computed by summing over the different clusters.Total WSS decreases with the number of clusters, as more centers yield partitions with more compact clusters.

Study cohorts' descriptions Avon Longitudinal Study of Parents and Children (ALSPAC)
2][3] Pregnant women in the ALSPAC cohort were recruited if they were Avon residents while pregnant, and their expected delivery dates lie between 1st April 1991 and 31st December 1992 (N = 14,541).Ethical approval for this study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees (a full list of the ethics committees that approved different aspects of the ALSPAC studies is available at http://www.bristol.ac.uk/alspac/researchers/research-ethics/).Data were collected during clinic visits or with postal questionnaires.Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time.Please note that the study website contains details of all the data that is available through a fully searchable data dictionary and variable search tool (http://www.bristol.ac.uk/alspac/researchers/our-data/.)

Alberta Pregnancy Outcomes and Nutrition (AProN) Study
The Alberta Pregnancy Outcomes and Nutrition (APrON) Study is a longitudinal cohort of pregnant women and their children living in the central and southern regions of Alberta, Canada. 4Pregnant women were recruited into the APrON cohort if they were at least 16 years old, able to speak and read English, of less than 27 gestational weeks, and willing to come for on-site clinic visits at the University of Calgary in Calgary, or the University of Alberta, in Edmonton, Alberta.A total of 2189 pregnant women were enrolled into the study between May 2009 and June 2012.1,945 participants (~88.9%)remained in the study when their children turned three.The APrON study was approved by the University of Calgary Health Research Ethics Board (REB14-1702) and the University of Alberta Health Research Ethics Biomedical Panel (Pro00002954).

Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN)
The Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) study is a prospective communitybased cohort of Canadian mother-child dyads. 5Pregnant women from Montreal, Quebec, and Hamilton, Ontario were recruited, if they were at least 18 years old and able to speak and read in either English or French.Subjects were excluded from the study if they had serious obstetric complications during pregnancy or delivery of the child, or if the child had extremely low birth weight, was premature (≤ 37 weeks' gestation) or had any congenital disease.Ethical approval for this study was obtained from the Douglas Mental Health University Institute (Montreal) and St-Joseph's Hospital (Hamilton).

Montreal Antenatal Well-being Study (MAWS)
The Montreal Antenatal Well-Being Study (MAWS) is a Quebec-based prospective longitudinal cohort designed to identify the biological, psychological, and social factors that contribute to maternal mental health and family well-being from pregnancy through early childhood.A community-based sample of 1130 pregnant participants between the ages of 18-45 was recruited from August 2019 to March 2021, either in person via phone recruitment from obstetric clinics or self-selection from online advertisements.All mothers have now delivered their babies with a reported 54 losses during pregnancy, mainly due to miscarriages or pregnancy termination.Detailed measures of maternal mental health, psychosocial factors and pregnancy health are collected twice during pregnancy and three times postpartum.Partners of participants were recruited at approximately 18 months postpartum concurrent with a detailed assessment of child development.Ethical approval for this study was obtained from the Research Ethics Board of the CIUSSS de l'Ouest de l'Île de Montréal. 6rowing Up in Singapore Towards healthy Outcomes (GUSTO) Pregnant women aged ≥ 18 years were approached to be enrolled into the Growing Up in Singapore Towards healthy Outcomes (GUSTO) longitudinal cohort study from hospital maternity units in Singapore, specifically KK Women's and Children's Hospital (KKH) and National University Hospital (NUH) between June 2009 and October 2010.7 Pregnant women who were Singapore Citizens or Singapore Permanent Residents, of < 14 gestational weeks, had both the intention to deliver at either hospital and reside in Singapore for the next 5 years were recruited into the study.Additionally, both parents and grandparents of the fetus must be of the same ethnicity.Women who had significant medical conditions (e.g.: Type 1 diabetes mellitus, psychosis), were on certain medication (e.g.: psychotropic drugs), and were on chemotherapy were excluded from the study.1,450 pregnant women were recruited, leading to 1,209 deliveries.Written informed consent was obtained from all participants.The study was approved by the National Health Care Group Domain Specific Review Board (D/09/02) and SingHealth Centralized Institutional Review Board (2009/280/D).

Singapore PREconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO)
Healthy women aged between 18 to 45 years were recruited into the Singapore PREconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO), a preconception, longitudinal cohort study in Singapore. 8ecruitment began between February 2015 and October 2017, from both the KK Women's and Children's Hospital and the public.Women of either Chinese, Malay, Indian or any combination of these 3 ethnic groups, who planned to conceive within 1 year of recruitment and had the intention to reside in Singapore for the next 5 years were recruited in the study.Women were excluded from this study if they fulfill any of the following criteria: were actively trying to conceive for more than 18 months; were using oral or implanted contraception; had an in situ intrauterine contraceptive device (IUCD) for the past 1 month; were undergoing fertility treatment (apart from those taking clomiphene or letrozole alone in the past 1 month); or had pre-existing health conditions (including established type 1 or type 2 diabetes, on systemic steroids, anticonvulsants, HIV or Hepatitis B or C medication in the past 1 month).1039 women were recruited, of which 475 became pregnant and 373 women delivered.Written informed consent was provided by participants.Ethical approval was obtained from the SingHealth Centralised Institutional Review Board (reference 2014/692/D).This study has been registered at ClinicalTrials.gov(NCT 03531658).

Mapping Antenatal Maternal Stress (MAMS)
The Mapping Antenatal Maternal Stress (MAMS) is a prospective longitudinal cohort study of pregnant women and their offspring in Singapore.The study recruited pregnant mothers, aged 21 -40 years, of 14 -24 gestational weeks, able to speak and read in English, having singletons and who had their obstetrician visits at the National University Hospital in Singapore.Women were excluded from the study if they met any of the following conditions: had pre-existing or a history of psychotic depression, schizophrenia, and bipolar disorders; had a history of thyroid disease; currently on steroids or thyroids medications; became pregnant via any assisted reproduction; or currently enrolled into any interventional randomized controlled trials.The study started in late September 2019 to December 2022.As of July 2022, there are 1329 pregnant women recruited into the study, with 1069 of them having delivered their children.Written informed consent was provided by the participants.The study was approved by the National Healthcare Group Domain Specific Review Board (2018/00967).

eTable 1 .
k-means algorithm.Red dashed lines refer to the optimal number of K clusters (x-axis) identified by an "elbow" in the scree plot, corresponding to the point with the greatest change in the clustering configuration as measured by the total WSS.ALSPAC: Avon Longitudinal Study of Parents and Children; APrON: Alberta Pregnancy Outcomes and Nutrition; MAWS: Montreal Antenatal Wellbeing Study; GUSTO: Growing Up in Singapore Towards healthy Outcomes; S-PRESTO: Singapore PREconception Study of Long-Term Maternal and Child Outcomes; MAMS: Mapping Antenatal Maternal Stress; MAVAN: Maternal Adversity, Vulnerability and Neurodevelopment; EPDS: Edinburgh Postnatal Depression Scale; CES-D: Center for Epidemiological Studies-Depression eFigure 2. Scree plots showing total WSS differences (diff-WSS) between consecutive values of the number of clusters.These plots approximate the slope of the total WSS, shown in the scree plots of eFigure 1, as a function of the number of clusters.The optimal number of clusters corresponds to the point where the slope of the scree plot stops increasing noticeably.The differences in total WSS are shown in the y-axis, while the xaxis indicates which clustering configurations are considered (i.e., lag K refers to the difference between the total WSS obtained with K+1 and K clusters).ALSPAC: Avon Longitudinal Study of Parents and Children; APrON: Alberta Pregnancy Outcomes and Nutrition; MAWS: Montreal Antenatal Wellbeing Study; GUSTO: Growing Up in Singapore Towards healthy Outcomes; S-PRESTO: Singapore PREconception Study of Long-Term Maternal and Child Outcomes; MAMS: Mapping Antenatal Maternal Stress; MAVAN: Maternal Adversity, Vulnerability and Neurodevelopment; EPDS: Edinburgh Postnatal Depression Scale; CES-D: Center for Epidemiological Studies-Depression eFigure 3. Trajectories of maternal depressive symptoms during the perinatal period.X-axis refers to time in years from pregnancy to postnatal period.Dashed vertical lines refer to childbirth.S-PRESTO: Singapore PREconception Study of Long-Term Maternal and Child Outcomes; MAMS: Mapping Antenatal Maternal Stress; MAVAN: Maternal Adversity, Vulnerability and Neurodevelopment; EPDS: Edinburgh Postnatal Depression Scale; CES-D: Center for Epidemiological Studies Depression eFigure 4. Trajectories of maternal depression when considering those with clinically-validated EPDS cut-offs for depression since pregnancy.X-axis refers to time in years from pregnancy to postnatal period.Dashed vertical lines refer to childbirth.S-PRESTO: Singapore PREconception Study of Long-Term Maternal and Child Outcomes; MAMS: Mapping Antenatal Maternal Stress; EPDS: Edinburgh Postnatal Depression Scale.Overview of time points when maternal depressive symptoms data were collected for this study © 2023 Kee MZL et al.JAMA Network Open.
MZL et al.JAMA Network Open.

eTable 3. Study characteristics for data used from the APrON cohort
Percentages are rounded off to nearest 0.1%.Common IDs refers to participants found at all stated timepoints and hence, used for analyses.PG2 and PG3 represent 2 nd and 3 rd trimester of pregnancy respectively.M08 and M21 represent 8-and 21-months postpartum respectively.refers to any combinations of the above-mentioned self-reported ethnicities.b refers to Arab, Caribbean, Central Asian and West Asian.*Percentages are rounded off to nearest 0.1%.Common IDs refers to participants found at all stated timepoints and hence, used for analyses.PG2 and PG3 represent 2 nd and 3 rd trimester of pregnancy respectively.M03, M06, M12 and M24 represent 3-, 6-, 12-and 24-months postpartum respectively.
© 2023 Kee MZL et al.JAMA Network Open. a

eTable 4. Study characteristics for data used from the MAWS cohort
© 2023 Kee MZL et al.JAMA Network Open.

Study characteristics for data used from the GUSTO cohort
a refers to Creole or any combinations of the above-mentioned self-reported ethnicities.b refers to Arab, Armenian, Persian, Malagasy, Middle Eastern, West Asian.*Percentages are rounded off to nearest 0.1%.Common IDs refers to participants found at all stated timepoints and hence, used for analyses.PG2 and PG3 represent 2 nd and 3 rd trimester of pregnancy respectively.M03 and M19 represent 3-and 19-months postpartum respectively.eTable 5. © 2023 Kee MZL et al.JAMA Network Open.

eTable 6. Study characteristics for data used from the S-PRESTO cohort ©
Percentages are rounded off to nearest 0.1%.Common IDs refers to participants found at all stated timepoints and hence, used for analyses.PG3 represent 3 rd trimester of pregnancy respectively.M03 and M24 represent 3-and 24-months postpartum respectively.2023 Kee MZL et al.JAMA Network Open.

eTable 7. Study characteristics for data used from the MAMS cohort ©
refers to any combinations of the above-mentioned self-reported ethnicities.*Percentages are rounded off to nearest 0.1%.Common IDs refers to participants found at all stated timepoints and hence, used for analyses.PG1, PG2 and PG3 represent 1 st , 2 nd and 3 rd trimester of pregnancy respectively.M03 and M6 represent 3-and 6-months postpartum respectively.2023 Kee MZL et al.JAMA Network Open. a

eTable 8. Study characteristics for data used from the MAVAN cohort
refers to any combinations of the above-mentioned self-reported ethnicities.* Percentages are rounded off to nearest 0.1%.Common IDs refers to participants found at all stated timepoints and hence, used for analyses.PG1 and PG3 represent 1 st and 3 rd trimester of pregnancy respectively.M03 and M6 represent 3-and 6-months postpartum respectively.
a © 2023 Kee MZL et al.JAMA Network Open.
refers to any combinations of the above-mentioned self-reported ethnicities.b refers to Arab.*Percentages are rounded off to nearest 0.1%.Common IDs refers to participants found at all stated timepoints and hence, used for analyses.PG3 represents 3 rd trimester of pregnancy respectively.M06, M12 and M24 represent 6-, 12-and 24-months postpartum respectively.